Building block forming a c-c or a c-hetero atom bond uponreaction

ABSTRACT

A building block having the dual capabilities of transferring genetic information and functional entity precursor to a recipient reactive group is disclosed. The building block may be used in the generation of a single complex or libraries of different complexes, wherein the complex comprises an encoded molecule linked to an encoding element. Libraries of complexes are useful in the quest for pharmaceutically active compounds.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a building block comprising acomplementing element and a precursor for a functional entity. Thebuilding block is designed to transfer the functional entity precursorwith an adjustable efficiency to a recipient reactive group uponrecognition between the complementing element and an encoding elementassociated with the reactive group. The invention also relates to amethod for transferring a functional entity precursor to recipient areactive group.

BACKGROUND

The transfer of a chemical entity from one mono-, di- or oligonucleotideto another has been considered in the prior art. Thus, N. M. Chung etal. (Biochim. Biophys. Acta, 1971, 228,536-543) used a poly(U) templateto catalyse the transfer of an acetyl group from 3′-O-acetyladenosine tothe 5′-OH of adenosine. The reverse transfer, i.e. the transfer of theacetyl group from a 5′-O-acetyladenosine to a 3′-OH group of anotheradenosine, was also demonstrated.

Walder et al. Proc. Natl. Acad. Sci. USA, 1979, 76, 51-55 suggest asynthetic procedure for peptide synthesis. The synthesis involves thetransfer of nascent immobilized polypeptide attached to anoligonucleotide strand to a precursor amino acid attached to anoligonucleotide. The transfer comprises the chemical attack of the aminogroup of the amino acid precursor on the substitution labile peptidylester, which in turn results in an acyl transfer. It is suggested toattach the amino acid precursor to the 5′0 end of an oligonucleotidewith a thiol ester linkage.

The transfer of a peptide from one oligonucleotide to another using atemplate is disclosed in Bruick RK et al. Chemistry & Biology, 1996,3:49-56. The carboxy terminal of the peptide is initially converted to athioester group and subsequently transformed to an activated thioesterupon incubation with Ellman's reagent. The activated thioester isreacted with a first oligo, which is 5′-thiol-terminated, resulting inthe formation of a thio-ester linked intermediate. The firstoligonucleotide and a second oligonucleotide having a 3′0 amino group isaligned on a template such that the thioester group and the amino groupare positioned in close proximity and a transfer is effected resultingin a coupling of the peptide to the second oligonucleotide through anamide bond.

SUMMARY OF THE INVENTION

The present invention relates to a building block of the generalformula:Complementing Element-Linker-Carrier-C—F-connecting group-Functionalentity precursorcapable of transferring a Functional entity precursor to a recipientreactive group, wherein

-   -   Complementing Element is a group identifying the Functional        entity precursor,    -   Linker is a chemical moiety comprising a spacer and a        S—C-connecting group, wherein the spacer is a valence bond or a        group distancing the Functional entity precursor to be        transferred from the complementing element and the        S—C-connecting group connects the spacer with the Carrier    -   Carrier is arylene, heteroarylene, C₁-C₆ alkylene, C₁-C₆        alkenylene, C₁-C₆ alkynylene, or —(CF₂)_(m)— substituted with        0-3 R¹ wherein m is an integer between 1 and 10;

R¹are independently selected from —H, —OR², —NR² ₂, —Halogen, —NO₂, —CN,—C(Halogen)₃, —C(O)R², —C(O)NHR², C(O)NR² ₂, —NC(O)R², —S(O)₂NHR²,—S(O)₂NR² ₂, —S(O)₂R², —P(O)₂—R², —P(O)—R², —S(O)—R², P(O)—OR²,—S(O)—OR², —N⁺R² ₃, wherein R² is H, C₁-C6 alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or aryl,

-   -   C—F-connecting group is chosen from the group consisting of        —SO₂—O—, —O—SO₂—O—, —C(O)—O—, —S⁺(R³RRrr)—, —C—U—C(V)—O—,        —P⁺(W)₂—O—, —P(W)—O— where U is —C(R²)₂, —NR²— or —O—; V is ═O        or ═NR² and W is —OR² or —N(R²)₂

Functional entity precursor is —C(H)(R³)—R⁴ or functional entityprecursor is heteroaryl or aryl optionally substituted with one or moresubstituents belonging to the group comprising R³ and R⁴.

Wherein R³ and R⁴ independently is H, alkyl, alkenyl, alkynyl,alkadienyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, optionallysubstituted with one or more substituents selected from the groupconsisting of SnR⁵R⁶R⁷, Sn(OR⁵)R⁶R⁷, Sn(OR⁵)(OR⁶)R⁷, BR⁵R⁶, B(OR⁵)R⁶,B(OR⁵)(OR⁶), halogen, CN, CNO, C(halogen)₃, OR⁵, OC(═O)R⁵, OC(═O)OR⁵,OC(═O)NR⁵R⁶, SR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, N₃, NR⁵R⁶,N⁺R⁵R⁶R⁷, NR⁵OR⁶, NR⁵NR⁶R⁷, NR⁵C(═O)R⁶ NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, NC,P(═O)(OR⁵)OR⁶, P⁺R⁵R⁶R⁷, C(═O)R⁵, C(═NR⁵)R⁶, C(═NOR⁵)R⁶, C(═NNR⁵R⁶),C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶, C(═O)NR⁵NR⁶R⁷, C(═NR⁵)NR⁶R⁷,C(═NOR⁵)NR⁶R⁷ or R⁸, wherein,

R⁵, R⁶, and R⁷ independently is H, alkyl, alkenyl, alkynyl, alkadienyl,cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, CN, CNO, C(halogen)₃, ═O, OR⁸, OC(═O)R⁸, OC(═O)OR⁸,OC(═O)NR⁸R⁹, SR⁸, S(═O)R⁸, S(═O)₂R⁸, S(═O)₂NR⁸R⁹, NO₂, N₃, NR⁸R⁹,N⁺R⁸R⁹R¹⁰, NR⁵OR⁸, NR⁵NR⁶R⁷, NR⁸C(═O)R⁹, NR⁸C(═O)OR⁹, NR⁸C(═O)NR⁹R¹⁰,NC, P(═O)(OR⁸)OR⁹, P⁺R⁵R⁶R⁷, C(═O)R⁸, C(═NR⁸)R⁹, C(═NOR⁸)R⁹, C(═NNR⁸R⁹),C(═O)OR⁸, C(═O)NR⁸R⁹, C(═O)NR⁸OR⁹ C(═NR⁵)NR⁶R⁷, C(═NOR⁵)NR⁶R⁷ orC(═O)NR⁸NR⁹R¹⁰, wherein R⁵ and R³ may together form a 3-8 memberedheterocyclic ring or R⁵ and R⁷ may together form a 3-8 memberedheterocyclic ring or R⁶ and R⁷ may together form a 3-8 memberedheterocyclic ring, wherein,

R⁸, R⁹, and R¹⁰ independently is H, alkyl, alkenyl, alkynyl, alkadienyl,cycloalkyl, 20 cycloheteroalkyl, aryl or heteroaryl and wherein R⁸ andR⁹ may together form a 3-8 membered heterocyclic ring or R⁸ and R¹⁰ maytogether form a 3-8 membered heterocyclic ring or R⁹ and R¹⁰may togetherform a 3-8 membered heterocyclic ring.

In the present description and claims, the direction of connectionsbetween the various components of a building block should be read leftto right. For example an S—C-connecting group —C(═O)—NH— is connected toa Spacer through the carbon atom on the left and to a Carrier throughthe nitrogen atom on the right hand side.

The term “C₃-C₇ cycloheteroalkyl” as used herein refers to a radical oftotally saturated heterocycle like a cyclic hydrocarbon containing oneor more heteroatoms selected from nitrogen, oxygen, phosphor, boron andsulphur independently in the cycle such as pyrrolidine (1-pyrrolidine;2-pyrrolidine; 3-pyrrolidine; 4-pyrrolidine; 5-pyrrolidine);pyrazolidine (1-pyrazolidine; 2-pyrazolidine; 3-pyrazolidine;4-pyrazolidine; 5-pyrazolidine); imidazolidine (1-imidazolidine;2-imidazolidine; 3-imidazolidine; 4 imidazolidine; 5-imidazolidine);thiazolidine (2-thiazolidine; 3-thiazolidine; 4-thiazolidine;5-thiazolidine); piperidine (1-piperidine; 2-piperidine; 3-piperidine;4-piperidine; 5-piperidine; 6-piperidine); piperazine (1-piperazine;2-piperazine; 3-piperazine; 4-piperazine; 5-piperazine; 6-piperazine);morpholine (2-morpholine; 3-morpholine; 4-morpholine; 5-morpholine;6-morpholine); thiomorpholine (2-thiomorpholine; 3-thiomorpholine;4-thiomorpholine; 5-thiomorpholine; 6-thiomorpholine); 1,2-oxathiolane(3-(1,2-oxathiolane); 4-(1,2-oxathiolane); 5-(1,2-oxathiolane);1,3-dioxolane (2-(1,3-dioxolane); 4-(1,3-dioxolane); 5(1,3dioxolane);tetrahydropyrane; (2-tetrahydropyrane; 3-tetrahydropyrane;4-tetrahydropyrane; 5-tetrahydropyrane; 6-tetrahydropyrane);hexahydropyridazine (1-(hexahydropyridazine); 2-(hexahydropyndazine);3-(hexahydropyridazine); 4-(hexahydropyridazine);5-(hexahydropyridazine); 6-(hexahydropyridazine)), [1,3,2]dioxaborolane,[1,3,6,2]dioxazaborocane

The term “aryl” as used herein includes carbocyclic aromatic ringsystems of 5-7 carbon atoms. Aryl is also intended to include thepartially hydrogenated derivatives of the carbocyclic systems as well asup to four fused fused aromatic- or partially hydrogenated rings, eachring comprising 5-7 carbon atoms.

The term “heteroaryl” as used herein includes heterocyclic unsaturatedring systems containing, in addition to 2-18 carbon atoms, one or moreheteroatoms selected from nitrogen, oxygen and sulphur such as furyl,thienyl, pyrrolyl, heteroaryl is also intended to include the partiallyhydrogenated derivatives of the heterocyclic systems enumerated below.

The terms “aryl” and “heteroaryl” as used herein refers to an aryl whichcan be optionally substituted or a heteroaryl which can be optionallysubstituted and includes phenyl, biphenyl, indenyl, naphthyl(1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl,N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl,3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl,3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl,xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl(2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6 quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyI), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl).

The Functional Entity carries elements used to interact with hostmolecules and optionally reactive elements allowing further elaborationof an encoded molecule of a library. Interaction with host moleculeslike enzymes, receptors and polymers is typically mediated through vander waal's interactions, polar- and ionic interactions and pi-stackingeffects. Substituents mediating said effects may be masked by methodsknown to an individual skilled in the art (Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis; 3rd ed.; John Wiley & Sons: NewYork, 1999.) to avoid undesired interactions or reactions during thepreparation of the individual building blocks and during librarysynthesis. Analogously, reactive elements may be masked by suitablyselected protection groups. It is appreciated by one skilled in the artthat by suitable protection, a functional entity may carry a wide rangeof substitutents.

The Functional Entity Precursor is a masked. Functional Entity that isincorporated into an encoded molecule. After incorporation, reactiveelements of the Functional Entity may be revealed by un-masking allowingfurther synthetic operations. Finally, elements mediating recognition ofhost molecules may be un-masked.

In a certain aspect of the invention, Functional entity precursor is—C(H)(R¹¹)—R¹¹′ or functional entity precursor is heteroaryl or arylsubstituted with 0-3 R¹¹, 0-3 R¹³ and 0-3 R¹⁵, wherein

R¹¹ and R¹¹′ are independently H, or selected among the group consistingof a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₈ alkynyl, C₄-C₈ alkadienyl, C₃-C₇cycloalkyl, C₃-C₇ cyclo-heteroalkyl, aryl, and heteroaryl, said groupbeing substituted with 0-3 R¹², 0-3 R¹³ and 0-3 R¹⁵,

or R¹¹ and R¹¹′0 are C₁-C₃ alkylene-NR¹² ₂, C₁-C₃ alkylene-NR¹²C(O)R¹⁶,C₁-C₃ alkylene-NR¹²C(O)OR¹⁶, C₁-C₂ alkylene-O—NR¹² ₂, C₁-C₂alkylene-O—NR¹²C(O)R¹⁶, C₁-C₂ alkylene-O—NR¹²C(O)OR¹⁶ substituted with0-3 R¹⁵,

-   -   where R¹² is H or selected independently among the group        consisting of C₁C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, heteroaryl, said group        being substituted with 0-3 R¹³ and 0-3 R¹⁵,    -   R¹³ is selected independently from —N₃, —CNO, —C(NOH)NH₂, —NHOH,        —NHNHR¹⁷, —C(O)R¹⁷, —SnR¹⁷ ₃, —B(OR¹⁷)₂, —P(O)(OR¹⁷)₂ or the        group consisting of C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₄-C₈        alkadienyl said group being substituted with 0-2 R¹⁴,    -   where R¹⁴ is independently selected from —NO₂, —C(O)OR¹⁷,        —COR¹⁷, —CN, —OSiR¹⁷ ₃, —OR¹⁷ and —NR¹⁷ ₂;    -   R¹⁵ is ═O, —F, —Cl, —Br, —I, —CN, —NO₂, —OR¹⁷, —NR¹⁷ ₂,        —NR¹⁷—C(O)R¹⁶, —NR¹⁷—C(O)OR¹⁶, —SR¹⁷, —S(O)R¹⁷, —S(O)₂R¹⁷,        —COOR¹⁷, —C(O)NR¹⁷ ₂ and —S(O)₂NR¹⁷ ₂,    -   R¹⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, aryl or C₁-C₆ alkylene-aryl substituted with 0-3        substituents independently selected from —F, —Cl, —NO₂, —R²,        —R², —SiR² ₃;

R¹⁷ is selected independently from H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,aryl, C₁-C₆ alkylene-aryl,

G is H or C₁-C₆ alkyl and n is 1,2,3 or 4.

The function of the carrier is to ensure the transferability of thefunctional entity precursor. To adjust the transferability a skilledchemist can design suitable substitutions of the carrier by evaluationof initial attempts. The transferability may be adjusted in response tothe chemical composition of the functional entity precursor, to thenature of the complementing element, to the conditions under which thetransfer and recognition is performed, etc.

In a preferred embodiment, the carrier is selected from the groupconsisting of arylene, heteroarylene or —(CF₂)_(m)— substituted with 0-3R¹ wherein m is an integer between 1 and 10, and C—F-connecting group is—SO₂—O—. Due to the high reactivity of such compounds a broad range ofrecipient reactive groups may be employed in the construction ofcarbon-carbon bonds or carbon-hetero atom bonds.

In another preferred embodiment of the invention, the carrier is—(CF₂)_(m)— wherein m is an integer between 1 and 10, the C—F-connectinggroup is —SO₂—O—; and the functional entity precursor is aryl orheteroaryl substituted with 0-3 R¹¹, 0-3 R¹³ and 0-3 R¹⁵.

The C—F-connecting group determines in concert with the carrier thetransferability of the functional entity precursor. In a preferredembodiment, the C—F-connecting group is —S⁺(R¹¹)—,

In another preferred embodiment, the C—F-connecting group is chosen fromthe group consisting of —SO₂—O—, and —S⁺(R¹⁷)—; wherein R¹⁷ is selectedindependently from H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, C₁-C₆alkylene-aryl.

In the presence of a catalyst comprising transition metals such as Pd,Ni or Cu, an aromatic moiety may be transferred from the C—F-connectinggroup to a recipient reactive group. Further, the transfer may beinitiated by adding the catalyst, independently of the annealing ofencoding - and complementing elements.

The S—C-connecting group provide a means for connecting the Spacer andthe Carrier. As such it is primarily of synthetic convenience and doesnot influence the function of a building block.

The spacer serves to distance the functional entity precursor to betransferred from the bulky complementing element. Thus, when present,the identity of the spacer is not crucial for the function of thebuilding block. It may be desired to have a spacer which can be cleavedby light. In this case, the spacer is provided with e.g. the group

In the event an increased hydrophilicity is desired the spacer may beprovided with a polyethylene glycol part of the general formula:

In a preferred embodiment, the complementing element serves the functionof transferring genetic information e.g. by recognising a codingelement. The recognition implies that the two parts are capable ofinteracting in order to assemble a complementing element—coding elementcomplex. In the biotechnological field a variety of interactingmolecular parts are known which can be used according to the invention.Examples include, but are not restricted to protein-proteininteractions, protein-polysaccharide interactions, RNA-proteininteractions, DNA-DNA interactions, DNA-RNA interactions, RNA-RNAinteractions, biotin-streptavidin interactions, enzyme-ligandinteractions, antibody-ligand interaction, protein-ligand interaction,etc.

The interaction between the complementing element and coding element mayresult in a strong or a weak bonding. If a covalent bond is formedbetween the parties of the affinity pair the binding between the partscan be regarded as strong, whereas the establishment of hydrogenbondings, interactions between hydrophobic domains, and metal chelationin general results in weaker bonding. In general relatively weak bondingis preferred. In a preferred aspect of the invention, the complementingelement is capable of reversible interacting with the coding element soas to provide for an attachment or detachment of the parts in accordancewith the changing conditions of the media.

In a preferred aspect of the invention, the interaction is based onnucleotides, i.e. the complementing element is a nucleic acid.Preferably, the complementing element is a sequence of nucleotides andthe coding element is a sequence of nucleotides capable of hybridisingto the complementing element. The sequence of nucleotides carries aseries of nucleobases on a backbone. The nucleobases may be any chemicalentity able to be specifically recognized by a complementing entity. Thenucleobases are usually selected from the natural nucleobases (adenine,guanine, uracil, thymine, and cytosine) but also the other nucleobasesobeying the Watson-Crick hydrogen-bonding rules may be used, such as thesynthetic nucleobases disclosed in U.S. Pat. No. 6,037,120. Examples ofnatural and non-natural nucleobases able to perform a specific pairingare shown in FIG. 2. The backbone of the sequence of nucleotides may beany backbone able to aggregate the nucleobases is a sequence. Examplesof backbones are shown in FIG. 4. In some aspects of the invention theaddition of non-specific nucleobases to the complementing element isadvantegeous, FIG. 3

The coding element can be an oligonucleotide having nucleobases whichcomplements and is specifically recognised by the complementing element,i.e. in the event the complementing element contains cytosine, thecoding element part contains guanine and visa versa, and in the eventthe complementing element contains thymine or uracil the coding elementcontains adenine.

The complementing element may be a single nucleobase. In the generationof a library, this will allow for the incorporation of four differentfunctional entities into the template-directed molecule. However, toobtain a higher diversity a complementing element preferably comprisesat least two and more preferred at least three nucleotides.Theoretically, this will provide for 42 and 43, respectively, differentfunctional entities uniquely identified by the complementing element.The complementing element will usually not comprise more than 100nucleotides. It is preferred to have complementing elements with asequence of 3 to 30 nucleotides.

The building blocks of the present invention can be used in a method fortransferring a functional entity precursor to a recipient reactivegroup, said method comprising the steps of

-   -   providing one or more building blocks as described above and    -   contacting the one or more building blocks with a corresponding        encoding element associated with a recipient reactive group        under conditions which allow for a recognition between the one        or more complementing elements and the encoding elements, said        contacting being performed prior to, simultaneously with, or        subsequent to a transfer of the functional entity precursor to        the recipient reactive group.

The encoding element may comprise one, two, three or more codons, i.e.sequences that may be specifically recognised by a complementingelement. Each of the codons may be separated by a suitable spacer group.Preferably, all or at least a majority of the codons of the template arearranged in sequence and each of the codons are separated from aneighbouring codon by a spacer group. Generally, it is preferred to havemore than two codons on the template to allow for the synthesis of morecomplex encoded molecules. In a preferred aspect of the invention thenumber of codons of the encoding element is 2 to 100. Still morepreferred are encoding elements comprising 3 to 10 codons. In anotheraspect, a codon comprises 1 to 50 nucleotides and the complementingelement comprises a sequence of nucleotides complementary to one or moreof the encoding sequences.

The recipient reactive group may be associated with the encoding elementin any appropriate way. Thus, the reactive group may be associatedcovalently or noncovalently to the encoding element. In one embodimentthe recipient reactive group is linked covalently to the encodingelement through a suitable linker which may be separately cleavable torelease the reaction product. In another embodiment, the reactive groupis coupled to a complementing element, which is capable of recognising asequence of nucleotides on the encoding element, whereby the recipientreactive group becomes attached to the encoding element byhybridisation. Also, the recipient reactive group may be part of achemical scaffold, i.e. a chemical entity having one or more reactivegroups available for receiving a functional entity precursor from abuilding block.

The recipient reactive group may be any group able to participate incleaving the bond between the carrier and the functional entityprecursor to release the functional entity precursor. Typically, therecipient reactive group is a nucleophilic atom such as S, N, 0, C or P.Scheme 1a shows the transfer of an alkyl group and scheme 1b shows thetransfer of an vinyl group.

Alternatively, the recipient reactive group is a organometallic compoundas shown in scheme 2.

According to a preferred aspect of the invention the building blocks areused for the formation of a library of compounds. The complementingelement of the building block is used to identify the functional entity.Due to the enhanced proximity between reactive groups when thecomplementing entity and the encoding element are contacted, thefunctional entity precursor together with the identity programmed in thecomplementing element is transferred to the encoding element associatedwith recipient reactive group. Thus, it is preferred that the sequenceof the complementing element is unique in the sense that the samesequence is not used for another functional entity. The uniqueidentification of the functional entity enable the possibility ofdecoding the encoding element in order to determine the synthetichistory of the molecule formed. In the event two or more functionalentities have been transferred to a scaffold, not only the identity ofthe transferred functional entities can be determined. Also the sequenceof reaction and the type of reaction involved can be determined bydecoding the encoding element. Thus, according to a preferred embodimentof the invention, each different member of a library comprises acomplementing element having a unique sequence of nucleotides, whichidentifies the functional entity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Two setups for Functional Entity Transfer

FIG. 2. Examples of specific base pairing

FIG. 3. Example of non-specific base-pairing

FIG. 4. Backbone examples

FIG. 5 Three examples of building blocks

DETAILED DESCRIPTION OF THE INVENTION

A building block of the present invention is characterized by itsability to transfer its functional entity precursor to a recipientreactive group. This is done by forming a new covalent bond between therecipient reactive group and cleaving the bond between the carriermoiety and the functional entity precursor of the building block.

Two setups for generalized functional entity precursor transfer from abuilding block are depicted in FIG. 1. In the first example, onecomplementing element of a building block recognizes a coding elementcarrying another functional entity precursor, hence bringing thefunctional entities in close proximity. This results in a reactionbetween functional entity precursor 1 and 2 forming a covalent bondbetween these concurrent with the cleavage of the bond betweenfunctional entity precursor 2 and its linker. In the second example, atemplate brings together two building blocks resulting in functionalentity precursor transfer from one building block to the other.

FIG. 5 illustrates three specific compounds according to the invention.For illustrative purposes the individual features used in the claims areindicated. The upper compound is an example of a building block whereinthe linker is backbone attached at the 3′-position. The first part ofthe linker, i.e. the spacer, is an aliphatic chain ending in a nitrogenatom. The nitrogen atom bridges to the S—C-connecting group, which is anN-acylated arylmethyleamine. The carrier attached to the left hand sidecarbonyl group of the S—C-connecting group is a benzene ring holding theC—F Connecting group in the para position. The C—F Connecting group is apositively charged sulfur atom which is attached to the FunctionalEntity Precursor, in this case a benzyl group. When the building blockis presented to a nucleophilic recipient reactive group, such an amineor a thiol, Functional Entity Precursor is transferred to benzylate therecipient reactive group.

The middle compound illustrates a 5′0 attachment of a linker. The linkeris linked through a phosphate group and extends into a three memberedaliphatic chain. Through another phosphate group and a PEG linker thecomplementing element is linked via an amide bond to the Carrier. Whenthe building block is presented to a nucleophile the Functional EntityPrecursor is transferred resulting in an alkylation of the nucleophile.

The lower compound illustrates a nucleobase attachment of the linker.The linker attaches to the 5 position of a pyrimidine type nucleobaseand extents through an α-β unsaturated N-methylated amide to theS—C-connecting group, which is a 4-amino methyl benzoic acid derivative.The functional entity precursor can be transferred to a nucleophilicrecipient reactive group e.g. an amine or a thiol forming an allylicamine or thiol.

According to the invention, the functional entity precursor is of theformula —C(H)(R³)—R⁴ or functional entity precursor is heteroaryl oraryl optionally substituted with one or more substituents belonging tothe group comprising R³ and R⁴. In a further preferred embodiment,

R³ and R⁴ independently is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₄-C₈ alkadienyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl orheteroaryl, optionally substituted with one or more substituentsselected from the group consisting of

SnR⁵R⁶, R⁷, Sn(OR⁵)R⁶R⁷, Sn(OR⁵)(OR⁶)R⁷, BR⁵R⁶, B(OR⁵)R⁶, B(OR⁵)(OR⁶),halogen, CN, CNO, C(halogen)₃, ═O, OR⁵, OC(═O)R⁵, OC(═O)OR⁵,OC(═O)NR⁵R⁶, SR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, N₃, NR⁵R⁶,N⁺R⁵R⁶R⁷, NR⁵OR⁶, NR⁵NR⁶R⁷, NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, NC,P(═O)(OR⁵)OR⁶, P⁺R⁵R⁶R⁷, C(═O)R⁵, C(═NR⁵)R⁶, C(═NOR⁵)R⁶, C(═NNR⁵R⁶),C(═O)OR, C(═O)NR⁵R⁶, C(═O)NR⁵OR₆, C(═O)NR⁵NR⁶R⁷, C(═NR⁵)NR⁶R⁷,C(═NOR⁵)NR⁶R⁷ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₄-C₈ alkadienyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl,aryl or heteroaryl and wherein R⁵ and R⁶ may together form a 3-8membered heterocyclic ring or R⁵ and R⁷ may together form a 3-8 memberedheterocyclic ring or R⁶ and R⁷ may together form a 3-8 memberedheterocyclic ring,

in another prefered embodiment,

R³ and R⁴ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl or heteroaryl, optionally substituted with one ormore substituents selected from the group consisting of halogen, CN,C(halogen)₃, ═O, OR⁵, OC(═O)R⁵, OC(═O)OR⁵, OC(═O)NR⁵R⁶, SR⁵, S(═O)R⁵,S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵OR⁶, NR5NR⁶R⁷, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, P(═O)(OR5)OR⁶, C(═O)R⁵, C(═NR⁵)R⁶,C(═NOR⁵)R⁶, C(═NNR⁵R⁶), C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶,C(═O)NR⁵NR⁶R⁷, C(═NR⁵)NR⁶R⁷, C(═NOR⁵)NR⁶R⁷ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl or heteroaryl, optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, OC(═O)R⁵, OC(═O)OR⁵, OC(═O)NR⁵R⁶, SR⁵, S(═O)R⁵, S(═O)₂R⁵,S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵R⁶, NR⁵NR⁶R⁷, NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶,NR⁵C(═O)NR⁶R⁷, P(═O)(OR⁵)OR⁶, C(═O)R⁶, C(═NR⁵)R⁶, C(═NOR⁵)R⁶,C(═NNR⁵R⁶), C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶, C(═O)NR⁵NR⁶R⁷,C(═NR⁵)NR⁶R⁷, C(═NOR⁵)NR⁶R⁷ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl or heteroaryl, optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, phenyl, naphtyl, thienyl, furyl,pyridyl, quinolinyl or isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁶ and R5 maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 38 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, phenyl, naphtyl, thienyl, furyl, pyridyl,quinolinyl or isoquinolinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶NR⁵C(═O)OR⁶,NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ orR⁵, wherein,

R⁵, R⁶, R⁷ and R³ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, phenyl or naphtyl optionally substitutedwith one or more substituents selected from the group consisting of F,Cl, CN, CF₃, ═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶,NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵,C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R6 and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, thienyl, furyl, pyridyl, quinolinyl orisoquinolinyl optionally substituted with one or more substituentsselected from the group consisting of F, Cl, CN, CF₃, ═O, OR⁵, S(═O)R⁵,S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, R⁵C(═O)R⁶, NR⁵C(═O)OR⁶,NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ orR⁸, wherein,

R⁵, R⁶, R⁷ and R⁵ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloheteroalkyl, aryl or heteroaryl and wherein R⁵ and R⁶ maytogether form a 3-8 membered heterocyclic ring or R⁵ and R⁷ may togetherform a 3-8 membered heterocyclic ring or R⁶ and R⁷ may together form a3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R^(6,)NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl, butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,thienyl, furyl, pyridinyl, quinolinyl or isoquinolinyl and wherein R⁵and R⁶ may together form a 3-8 membered heterocyclic ring or R⁵ and R⁷may together form a 3-8 membered heterocyclic ring or R⁶ and R⁷ maytogether form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R^(6,) R⁷ and R⁸ independently is H, methyl, ethyl, propyl, butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,thienyl, furyl, pyridinyl, quinolinyl or isoquinolinyl and wherein R⁵and R⁶ may together form a 3-8 membered heterocyclic ring or R⁵ and R⁷may together form a 3-8 membered heterocyclic ring or R⁶ and R⁷ maytogether form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, phenyl, naphtyl, thienyl, furyl, pyridyl,quinolinyl or isoquinolinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵s, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NRBR⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl, butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,thienyl, furyl, pyridinyl, quinolinyl or isoquinolinyl and wherein R⁵and R⁶ may together form a 3-8 membered heterocyclic ring or R⁵ and R⁷may together form a 3-8 membered heterocyclic ring or R⁶ and R⁷ maytogether form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, phenyl or naphtyl optionally substitutedwith one or more substituents selected from the group consisting of F,Cl, CN, CF₃, ═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶,NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶, NR⁵C(═O)NR R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵,C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl, butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,thienyl, furyl, pyridinyl, quinolinyl or isoquinolinyl and wherein R⁵and R⁶ may together form a 3-8 membered heterocyclic ring or R⁵ and R⁷may together form a 3-8 membered heterocyclic ring or R⁶ and R⁷ maytogether form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, thienyl, furyl, pyridyl, quinolinyl orisoquinolinyl optionally substituted with one or more substituentsselected from the group consisting of F, Cl, CN, CF₃, ═O, OR⁵, S(═O)R⁵,S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶,NR⁵C(═O)NR⁶R⁷, C(═O)R⁶, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ orR⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl, butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,thienyl, furyl, pyridinyl, quinolinyl or isoquinolinyl and wherein R⁵and R⁶ may together form a 38 membered heterocyclic ring or R⁵ and R⁷may together form a 3-8 membered heterocyclic ring or R⁶ and R⁷ maytogether form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl or butyl andwherein R⁵ and R⁶ may together form a 3-8 membered heterocyclic ring orR⁵ and R⁷ may together form a 3-8 membered heterocyclic ring or R⁶ andR⁷ may together form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NRR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl or butyl andwherein R⁵ and R⁶ may together form a 3-8 membered heterocyclic ring orR⁵ and R⁷ may together form a 3-8 membered heterocyclic ring or R⁶ andR⁷ may together form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, phenyl, naphtyl, thienyl, furyl, pyridyl,quinolinyl or isoquinolinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl or butyl andwherein R⁵ and R⁶ may together form a 3-8 membered heterocyclic ring orR⁵ and R⁷ may together form a 3-8 membered heterocyclic ring or R⁶ andR⁷ may together form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, phenyl or naphtyl optionally substitutedwith one or more substituents selected from the group consisting of F,Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶,NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵,C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl or butyl andwherein R⁵ and R⁶ may together form a 3-8 membered heterocyclic ring orR⁵ and R⁷ may together form a 3-8 membered heterocyclic ring or R⁶ andR⁷ may together form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is H, thienyl, furyl, pyridyl, quinolinyl orisoquinolinyl optionally substituted with one or more substituentsselected from the group consisting of F, Cl, CN, CF₃, ═O, OR⁵, S(═O)R⁵,S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶, NR⁶C(═O)OR⁶,NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ orR⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, methyl, ethyl, propyl or butyl andwherein R⁵ and R⁶ may together form a 3-8 membered heterocyclic ring orR⁵ and R⁷ may together form a 3-8 membered heterocyclic ring or R⁶ andR⁷ may together form a 3-8 membered heterocyclic ring,

in still another prefered embodiment,

R³ and R⁴ independently is methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁶R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁶)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl,

in still another prefered embodiment,

R³ and R⁴ independently is aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein, R⁵, R⁶, R⁷ and R⁸ independently is H,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

in still another prefered embodiment,

R³ and R⁴ independently is phenyl, naphtyl, thienyl, furyl, pyridyl,quinolinyl or isoquinolinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl,

in still another prefered embodiment,

R³ and R⁴ independently is phenyl or naphtyl optionally substituted withone or more substituents selected from the group consisting of F, Cl,CN, CF₃, ═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶,NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵,C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁸, R⁷ and R⁸ independently is H, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl,

in still another prefered embodiment,

R³ and R⁴ independently is thienyl, furyl, pyridyl, quinolinyl orisoquinolinyl optionally substituted with one or more substituentsselected from the group consisting of F, Cl, CN, CF₃, ═O, OR⁵, S(═O)R⁵,S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶,NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ orR⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl,

in still another prefered embodiment,

R³ and R⁴ independently is methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one ormore substituents selected from the group consisting of F, Cl, CN, CF₃,═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, phenyl, naphthyl, thienyl, furyl,pyridinyl, quinolinyl or isoquinolinyl,

in still another prefered embodiment,

R³ and R⁴ independently is aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, phenyl, naphthyl, thienyl, furyl,pyridinyl, quinolinyl or isoquinolinyl,

in still another prefered embodiment,

R³ and R⁴ independently is phenyl, naphtyl, thienyl, furyl, pyridyl,quinolinyl or isoquinolinyl optionally substituted with one or moresubstituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁶,NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, phenyl, naphthyl, thienyl, furyl,pyridinyl, quinolinyl or isoquinolinyl,

in still another prefered embodiment,

R³ and R⁴ independently is phenyl or naphtyl optionally substituted withone or more substituents selected from the group consisting of F, Cl,CN, CF₃, ═O, OR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶,NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵,C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ or R⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, phenyl, naphthyl, thienyl, furyl,pyridinyl, quinolinyl or isoquinolinyl,

in still another prefered embodiment,

R³ and R⁴ independently is thienyl, furyl, pyridyl, quinolinyl orisoquinolinyl optionally substituted with one or more substituentsselected from the group consisting of F, Cl, CN, CF₃, ═O, OR⁵, S(═O)R⁵,S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, NR⁵R⁶, NR⁵C(═O)R⁵, NR⁵C(═O)OR⁶,NR⁵C(═O)NR⁶R⁷, C(═O)R⁵, C(═NOR⁵)R⁶, C(═O)OR⁵, C(═O)NR⁵R⁶, C(═O)NR⁵OR⁶ orR⁸, wherein,

R⁵, R⁶, R⁷ and R⁸ independently is H, phenyl, naphthyl, thienyl, furyl,pyridinyl, quinolinyl or isoquinolinyl,

in still another prefered embodiment,

R³ and R⁴ independently is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl or heteroaryl

in still another prefered embodiment,

R³ and R⁴ independently is H,

in still another prefered embodiment,

R³ and R⁴ independently is C₁-C₆ alkyl, C₃-C₇ cycloalkyl or C₃-C₇cycloheteroalkyl,

in still another prefered embodiment,

R³ and R⁴ independently is methyl, ethyl, propyl or butyl

in still another prefered embodiment

R³ and R⁴ independently is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl

in still another prefered embodiment

R³ and R⁴ independently is aziridinyl, pyrrolidinyl, piperidinyl ormorpholinyl

in still another prefered embodiment,

R³ and R⁴ independently is aryl or heteroaryl

in still another prefered embodiment,

R³ and R⁴ independently is phenyl or naphthyl

in still another prefered embodiment,

R³ and R⁴ independently is thienyl, furyl, pyridyl, quinolinyl orisoquinolyl

Experimental Section

General Procedure 1: Preparation of Carrier-Functional Entity Reagents:

The 4-halobenzoic acid (25 mmol) is added to a ice cooled solution ofchloro sulfonic acid (140 mmol). The mixture is slowly heated to refluxand left at reflux for 2-3 hours. The mixture is added to 100 mL ice andthe precipitate collected by filtration. The filtrate is washed withwater (2×50 mL) and the dried in vacuo affording the correspondingsulfonoyl chloride in 60-80% yield. The 3-chlorosulfonyl-4-halo-benzoicacid derivate (5 mmol) is dissolved in EtOH (5 mL) and added to a icecooled mixture of NaOEt (10 mL, 2M). The mixture is stirred o/n at rt.Acetic acid (40 mmol) is added and the mixture is evaporated in vacuo.Water (10 mL) is added and pH adjusted to pH=2 (using 1M HCl). Theproduct is extracted with DCM (2×25 mL), dried over Na₂SO₄ andevaporated in vacuo affording the desired products.

EXAMPLE 1 General Procedure (1)

3-Ethoxysulfonyl4-fluorobenzoic acid

¹H-NMR (DMSO-d₆): δ 8.49 (d, 1H), 7.85 (dd, 1H), 7.5 (d, 1H), 4.32 (q,2H), 1.32 (t, 3H)

EXAMPLE 2 General Procedure (1)

4-chloro-3-Ethoxysulfonylbenzoic acid

¹H-NMR (DMSO-d₆): δ 8.49 (d, 1H), 7.85 (dd, 1H), 7.5 (d, 1H), 4.32 (q,2H), 1.32 (t, 3H)

EXAMPLE 3

4-Methylsulfanyl benzoic acid (0.5 g, 2.97 mmol, commercially availablefrom Aldrich, cat no. 145521) was added to methyl p-toluene solfunate(0.61 g, 3.27 mmol). The mixture was heated to 140° C. for 1 hour in asealed vessel. After cooling to rt the mixture was trituated withdiethyl ether. Filtration and drying in vacuo yielded 844 mg (80%) ofthe desired product (>95% pure by ¹H nmr).

¹H nmr (DMSO-d6): 8.20-8.10 (m, 4H), 7.45 (d, 2H), 7.08 (d, 2H), 3.29(s, 6H), 2.30 (s, 3H).General Procedure 2: Solid Phase Preparation of Carrier-FunctionalEntity Reagents for Alkylation Building Blocks:

Ps=Polystyrene resin. Alternatively other acid labile linkers may beemployed.

Step 1:

A polystyrene resin with a wang linker (4-hydroxymethylphenol linker)(50mg˜50 umol), a bi-functional carrier (200 umol, 4 equiv) in a solventsuch as THF, DCM, DCE, DMF, NMP or a mixture thereof (500 uL) and a basesuch as TEA, DIEA, pyridine (400 umol, 8 equiv), optionally in thepresence of DMAP (100 umol), are allowed to react at temperaturesbetween −20° C. and 60° C., preferably between 0° C. and 25° C., for1-24 h, preferably 14 h. The resin is washed with the solventcomposition used during the reaction (5×1 mL) and used in the followingstep.

Step 2:

A functional entity precursor carrying a hydroxy group in the positionof the intended attachment to the C—F-connecting group (200 umol, 4equiv) in a solvent such as THF, DCM, DCE, DMF, NMP or a mixture thereof(500 uL) and a base such as TEA, DIEA, pyridine (400 umol, 8 equiv),optionally in the presence of DMAP, are added to the resin bound carrierisolated in step 1 and allowed to react at temperatures between 0° C.and 100° C., preferably between 25° C. and 80° C., for 248 h,preferably. 4-16 h. The resin is washed with the solvent compositionused during the reaction (5×1 mL).

Step 3:

The desired Carrier-Functional entity reagent is cleaved from the resinobtained in step 2 by treatment with an acid like TFA, HF or HCl in asolvent such as THF, DCM, DCE or a mixture thereof (1 mL) attemperatures between −20° C. and 60° C., preferably between 0° C. and25° C., for 14 h, preferably 1-2 h. Upon filtration, the resin is washedwith the solvent composition used during cleavage (2×1 mL) and thecombined filtrates are evaporated in vacuo. The isolated product may bepurified by chromatography.

Assembly of Building Blocks

The Carrier-Functional entity reagent may be bound to the Spacer byseveral different reactions as illustrated below.

Formation of an Amide Bond Between a Carboxylic Acid of the Carrier andan Amine Group of a Spacer

General Procedure 3: Preparation of Building Blocks by Loading aCarrier-Functional Entity Reagent onto a Nucleotide DerivativeComprising an Amino Group:

15 uL of a 150 mM building block solution of FE¹-Carrier-COOH is mixedwith 15 μL of a 150 mM solution of EDC and 15 μL of a 150 mM solution ofN-hydroxy-succinimide (NHS) using solvents like DMF, DMSO, water,acetonitril, THF, DCM, methanol, ethanol or a mixture thereof. Themixture is left for 15 min at 25° C. 45 μL of an aminooligo (10 nmol) in100 mM buffer at a pH between 5 and 10, preferably 6.0-7.5 is added andthe reaction mixture is left for 2 hours at 25° C. Excess building blockand organic by-products were removed by extraction with EtOAc (400 μL).Remaining EtOAc is evaporated in vacuo using a speedvac. The buildingblock is purified following elution through a BiORad micro-spinchromatography column, and analyzed by electron spray mass spectrometry(ES-MS).

EXAMPLE 4 General Procedure ( )

Where Oligo is 5′0 XCG ATG GAT GCT CCA GGT CGC 3′, X=5′ amino C₆ (Glencatalogue# 10-1906-90), Expected molecular weight: 6313.22 MS(calc.)=6543,43; MS (found)=6513,68** Observed molecular weight of the cleaved sulfonic ester: 6513.68Expected molecular weight of the cleaved ester. 6514.37 The quantitativeloss of the ethyl group Is probably due to the presence of pipeddineduring the recording of the LCMS data.

General Procedure 4: Loading of a Carrier Coupled Functional Entity ontoan Amino Ontgo:

25 μl 100 mM carrier coupled functional entity dissolved in DMF(dimethyl formamide) was mixed with 25 μl 100 mM EDC(1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride) in DMF for30 minutes at 25° C. The mixture was added to 50 μl amino oligo in H₂Owith 100 mM HEPES (2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethanesulfonicacid) pH 7.5 and the reaction was allowed to proceed for 20 minutes at25° C. Unreacted carrier coupled functional entity was removed byextraction with 500 μl EtOAc (ethyl acetate), and the oligo was purifiedby gel filtration through a microspin column equilibrated with 100 mMMES (2-(N-morpholino) ethanesulfonic acid) pH 6.0.

Oligonucleotide used:

Oligo A: 5′-YACGATGGATGCTCCAGGTCGC

Y=Amino modifier C6 (Glen#10-1906)

EXAMPLE 5 General Procedure 4

Carrier—Functional Entity: (4-Carboxy-phenyl)-dimethyl-sulfonium

Mass: 6789.21 (observed using ES-MS), 6790.65 (calculated)General Procedure 5: Preparation of Arylation Building Blocks:

Funtional Entity-OH is a phenol, n is an integer between 3 and 6.Step 1

To a solution of the bis-sulfonylchloride (Ward, R. B.; J. Org. Chem.;30; 1965; 3009-3011; Qiu, Weiming; Burton, Donald J.; J. Fluorine Chem.;60; 1; 1993; 93100)(3 umol) in DMF, DMSO, acetonitril, THF or a mixturethereof (150 uL) is a phenolic functional entity in excess (1.05-1.8mmol) in DMF, DMSO, acetonitril, THF or a mixture thereof (150 uL) addedslowly at temperatures between −20° C. and 100° C. preferably at 0-50°C. in the presence of a base such as TEA, DIEA, pyridine, Na-HCO₃ orK₂CO₃.

Step2

The reaction mixture from step 1 is added to a solution of an aminooligo(10 nmol) in 100 mM buffer at a pH between 5 and 10, preferably 6.0-7.5optionally in the presence of NHS. The reaction mixture is left for 2hours at 25° C. Excess building block and organic by-products wereremoved by extraction with EtOAc (400 μL). Remaining EtOAc is evaporatedin vacuo using a speedvac. The building aminooligo is purified followingelution through a BiORad micro-spin chromatography column, and analyzedby electron spray mass spectrometry (ES-MS).

Use of Building Blocks

General Procedure 6: Alkylation of Oligonucleotide DerivativesContaining a Nucleophilic Recipient Group Using a Building Block of theInvention:

An oligonucleotide building block carrying functional entity FE¹ iscombined at 2 μM final concentration with one equivalent of acomplementary building block displaying a nucleophilic recipient group.Reaction proceeds at temperatures between 0° C. and 100° C. preferablybetween 15° C.-50° C. for 148 hours, preferably 10-20 hours in DMF,DMSO, water, acetonitril, THF, DCM, methanol, ethanol or a mixturethereof, pH buffered to 4-10, preferably 6-8. Organic by-products areremoved by extraction with EtOAc, followed by evaporation of residualorganic solvent for 10 min in vacuo. Pd catalyst is removed andoligonucleotides are isolated by eluting sample through a BiORadmicro-spin chromatography column. Coupling efficiency is quantified byES-MS analysis.

General Procedure 7: Transfer of Functional Entity from a Carrier Oligoto Recipient Reactive Group.

A carrier coupled functional entity oligo (Example 1)(250 pmol) wasadded to a scaffold oligo B (200 pmol) in 50 μl 100 mM MES, pH 6. Themixture was incubated overnight at 25° C. Subsequently, the mixture waspurified by gel filtration using a microspin column equilibrated withH₂O and transfer of the functional entity was verified by electron spraymass spectrometry (ES-MS). Transfer efficiency is expressed in percentand were calculated by dividing the abundance of scaffold oligo carryingtransferred functional entities to total abundance of scaffold oligos(with and without transferred functional entities).

EXAMPLE 6 General Procedure 7

Mass (“X”): 6583.97 (observed), 6583.31 (calculated). Abundance: 65.79(arbitrary units)

Mass (“Y”): 6599.73 (observed), 6597.34 (calculated). Abundance: 29.23(arbitrary units)

Mass (“Z”): 6789.36 (observed), 6790.65 (calculated)

Transfer efficiency calculated as: 29.23/ (29.23+65.79) ═0.3076˜31%General Procedure 8: Arylation of Oligonucleotide Derivatives Containinga Nucleophilic Recipient Group Using a Building Block of the Invention:

An oligonucleotide building block carrying functional entity FE¹ iscombined at 2 μM final concentration with one equivalent of acomplementary building block displaying a nucleophilic recipient group.In the presence of a Pd catalyst, the reaction proceeds at temperaturesbetween 0° C. and 100° C. preferably between 15° C.-50° C. for 1-48hours, preferably 10-20 hours in DMF, DMSO, water, acetonitrile, THF,DCM, methanol, ethanol or a mixture thereof, pH buffered to 4-10,preferably 6-8. Organic by-products are removed by extraction withEtOAc, followed by evaporation of residual organic solvent for 10 min invacuo. Pd catalyst is removed and oligonucleotides are isolated byeluting sample through a BiORad micro-spin chromatography column.Coupling efficiency is quantified by ES-MS analysis.General Procedure 9: General Route to the Formation ofAlkylating/Vinylating Monomer Building Blocks with a Thio-SuccinimidS—C-Connecting Group and Use of These:

R¹ and R² may be used to tune the reactivity of the sulphate to allowappropriate reactivity. Chloro and nitro substitution will increasereactivity. Alkyl groups will decrease reactivity. Ortho substituents tothe sulphate will due to steric reasons direct incoming nucleophiles toattack the R-group selectively and avoid attack on sulphur. E.g.

3-Aminophenol (6) is treated with maleic anhydride, followed bytreatment with an acid e.g. H₂SO₄ or P₂O₅ and heat to yield themaleimide (7). The ring closure to the maleimide may also be achievedwhen an acid stable O-protection group is used by treatment with or Ac₂Owith or without heating, followed by O-deprotection. Alternativelyreflux in Ac₂O, followed by O-deacetylation in hot water/dioxane toyield (7).

Further treatment of (7) with SO₂Cl₂ with or without triethylamine orpotassium carbonate in dichloromethane or a higher boiling solvent willyield the intermediate (8), which may be isolated or directly furthertransformed into the aryl alkyl sulphate by the quench with theappropriate alcohol, in this case MeOH, whereby (9) will be formed. Theorganic building block (9) may be connected to an oligo nucleotide, asfollows.

A thiol carrying oligonucleotide in buffer 50 mM MOPS or hepes orphosphate pH 7.5 is treated with a 1-100 mM solution and preferably 7.5mM solution of the organic building block (9) in DMSO or alternativelyDMF, such that the DMSO/DMF concentration is 5-50%, and preferably 10%.The mixture is left for 1-16 h and preferably 24 h at 25° C. To give thealkylating in this case methylating monomer building block (10).

The reaction of the alkylating monomer building block (10) with an aminecarrying monomer building block may be conducted as follows:

The coding oligonucleotide (1 nmol) is mixed with a thio oligonucleotideloaded with a building block (1 nmol)(10) and an amino-oligonucleotide(1 nmol) in hepes-buffer (20 μL of a 100 mM hepes and 1 M NaCl solution,pH=7.5) and water (39 uL). The oligonucleotides are annealed to thetemplate by heating to 50° C. and cooled (2° C./second) to 30° C. Themixture is then left o/n at a fluctuating temperature (10° C. for 1second then 35° C. for 1 second), to yield the template boundmethylamine (11).

A vinylating monomer building block may be prepared and used similarilyas described above for an alkylating monomer building block. Althoughinstead of reacting the chlorosulphonate (8 above) with an alcohol, theintermediate chlorosulphate is isolated and treated with an enolate orO-trialkylsilylenolate with or without the presence of fluoride. E.g.

Formation of the vinylating monomer building block (13):

The thiol carrying oligonucleotide in buffer 50 mM MOPS or hepes orphosphate pH 7.5 is treated with a 1-100 mM solution and preferably 7.5mM solution of the organic building block (12) in DMSO or alternativelyDMF, such that the DMSO/DMF concentration is 5-50%, and preferably 10%.The mixture is left for 1-16 h and preferably 2-4 h at 25° C. To givethe vinylating monomer building block (13).

The sulfonylenolate (13) may be used to react with amine carryingmonomer building block to give an enamine (14a and/or 14b) or e.g. reactwith an carbanion to yield (15a and/or 15b). E.g.

The reaction of the vinylating monomer building block (13) and an amineor nitroalkyl carrying monomer building block may be conducted asfollows:

The coding oligonucleotide (1 nmol) is mixed with a oligonucleotidebuilding block (1 nmol)(13) and an amino-oligonucleotide (1 nmol) ornitroalkyl-oligonucleotide (1 nmol) in 0.1 M TAPS, phosphate orhepes-buffer and 300 mM NaCl solution, pH=7.5-8.5 and preferably pH=8.5.The oligonucleotides are annealed to the template by heating to 50° C.and cooled (2° C./second) to 30° C. The mixture is then left o/n at afluctuating temperature (10° C. for 1 second then 35° C. for 1 second),to yield template bound (14a/b or 15a/b). DCCN,N′-Dicyclohexylcarbodiimide DhbtOH3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine DICDiisopropylcarbodiimide DIEA Diethylisopropylamin DMAP4-Dimethylaminopyridine DNA Deoxyribosenucleic Acid EDC1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide.HCl HATU2-(1H-7-Azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro-phosphate HOAt N-Hydroxy-7-azabenzotriazole HOBtN-Hydroxybenzotriazole LNA Locked Nucleic Acid NHS N-hydroxysuccinimidOTf Trifluoromethylsulfonate OTs Toluenesulfonate PNA Peptide NucleicAcid PyBoP Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluoro-phosphate PyBroP Bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate RNA Ribonucleic acid TBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetra- fluoroborateTEA Triethylamine RP-HPLC Reverse Phase High Performance LiquidChromatography TBDMS-Cl Tert-Butyldimethylsilylchloride 5-Iodo-dU5-iodo-deoxyriboseuracil TLC Thin layer chromatography (Boc)₂O Bocanhydride, di-tert-butyl dicarbonate TBAF Tetrabutylammonium fluorideSPDP Succinimidyl-propyl-2-dithiopyridyl

1. A building block of the general formulaComplementing Element-Linker-Carrier-C—F-connecting group—Functionalentity precursorcapable of transferring a Functional entity precursor toa recipient reactive group, wherein Complementing Element is a groupidentifying the Functional entity precursor, Linker is a chemical moietycomprising a spacer and a S—C-connecting group, wherein the spacer is avalence bond or a group distancing the Functional entity precursor to betransferred from the complementing element and the S—C-connecting groupconnects the spacer with the Carrier, Carrier is arylene, heteroarylene,C₁-C₆ alkylene, C₁-C₆ alkenylene, C₁-C₆ alkynylene, or —(CF₂)_(m)—substituted with 0-3 R¹ wherein m is an integer between 1 and 10; R¹ areindependently selected from the group consisting of —H, —OR², —NR² ₂,-Halogen, —NO₂, —CN, —C(Halogen)₃, —C(O)R², —C(O)NHR², C(O)NR² ₂,—NC(O)R², —S(O)₂NHR², —S(O)₂NR², —S(O)₂R², —P(O)₂—R², —P(O)—R²,—S(O)—R², P(O)—OR², —S(O)—OR², and —N⁺R² ₃, wherein R² is H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or aryl, C—F-connecting group isselected from the group consisting of —SO₂—O—, —O—SO₂—O—, —C(O)—O—,—S⁺(R³)—, —C—U—C(V)—O—, —P⁺(W)₂—O—, and —P(W)—O—, where U is —C(R²)₂—,—NR²— or —O—; V is ═O or ═NR² and W is —OR² or —N(R²)₂, Functionalentity precursor is —C(H)(R³)—R⁴ or functional entity precursor isheteroaryl or aryl optionally substituted with one or more substituentsbelonging to the group comprising R³ and R⁴, Wherein R³ and R⁴independently is H, alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl,cycloheteroalkyl, aryl or heteroaryl, optionally substituted with one ormore substituents selected from the group consisting of SnR⁵R⁶R⁷,Sn(OR⁵)R⁶R⁷, Sn(OR⁵)(OR⁶)R⁷, BR⁵R⁶, B(OR⁵)R⁶, B(OR⁵)(OR⁶), halogen, CN,CNO, C(halogen) ₃, OR⁵, OC(═O) R⁵, OC(═O)OR⁵, OC (═O) NR⁵R⁶, SR⁵, S(═O)R⁵, S(═O)₂R⁵, S(═O)₂NR⁵R⁶, NO₂, N₃, NR⁵R⁶, N⁺R⁵R⁶R⁷, NR⁵OR⁶, NR⁵N R⁶R⁷,NR⁵C(═O)R⁶, NR⁵C(═O)OR⁶, NR⁵C(═O)NR⁶R⁷, NC, P(═O)(OR⁵)OR⁶, P⁺R⁵R⁶R⁷,C(═O) R⁵, C(═NR⁵)R⁶, C(═NOR⁵)R⁶, C(═NNR⁶), C(═O)OR⁵, C(═O)NR⁵R⁶,C(═O)NR⁵OR⁶, C(═O)NR⁵NR⁶R⁷, C(═NR⁵)NR⁶R⁷, C(═NOR⁵)NR⁶R⁷ and R⁸, wherein,R⁵, R⁶, and R⁷ independently is H, alkyl, alkenyl, alkynyl, alkadienyl,cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, CN, CNO, C(halogen)₃, ═O, OR⁸, OC(═O)R⁸, OC(═O)OR⁸,OC(═O)NR⁸R⁹, SR⁸, S(═O)R⁸, S(═O)₂R⁸, S(═O)₂NR⁸R⁹, NO₂, N₃, NR⁸R⁹,N⁺R⁸R⁹R¹⁰, NR⁵OR⁶, NR⁵NR⁶R⁷, NR⁸C(═O)R⁹, NR⁸C(═O)OR⁹, NR⁸C(═O)NR⁹R¹⁰,NC, P(═O)(OR⁸)OR⁹, P⁺R⁵R⁶R⁷, C(═O)R⁸, C(═NR⁸)R⁹, C(═NOR⁸)R⁹, C(═NNR⁸R⁹),C(═O)OR⁸, C(═O)NR⁸R⁹, C(═O)NR⁸OR⁹C(═NR⁵)NR⁶R⁷, C(═NOR⁵)NR⁶R⁷ orC(═O)NR⁸NR⁹R¹⁰, wherein R⁵ and R⁶ may together form a 3-8 memberedheterocyclic ring or R⁵ and R⁷ may together form a 3-8 memberedheterocyclic ring or R⁶ and R⁷ may together form a 3-8 memberedheterocyclic ring, wherein, R⁸, R⁹, and R¹⁰ independently is H, alkyl,alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloheteroalkyl, aryl orheteroaryl and wherein R⁸ and R⁹ may together form a 3-8 memberedheterocyclic ring or R⁸ and R¹⁰ may together form a 3-8 memberedheterocyclic ring or R⁹ and R¹⁰ may together form a 3-8 memberedheterocyclic ring.
 2. A compound according to claim 1 wherein,Functional entity precursor is —C(H)(R¹¹)—R¹¹′ or functional entityprecursor is heteroaryl or aryl substituted with 0-3 R¹¹, 0-3 R¹³ and0-3 R¹⁵, wherein R¹¹ and R¹¹′0 are independently H, or selected from thegroup consisting of a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₄-C₈alkadienyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, andheteroaryl, said group being substituted with 0-3 R¹², 0-3 R¹³ and 0-3R¹⁵, or R¹¹ and R¹¹′ are C₁-C₃ alkylene-NR¹² ₂, C₁-C₃alkylene-NR¹²C(O)R¹⁶, C₁-C₃ alkylene-NR¹²C(O)OR¹⁶, C₁-C₂ alkylene-O—NR¹²², C₁-C₂ alkylene-O—N R¹²C(O)R¹⁶, or C₁-C₂ alkylene-O—NR¹²C(O)OR¹⁶substituted with 0-3 R¹⁵, where R¹² is H or selected independently fromthe group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, and heteroaryl, said groupbeing substituted with 0-3 R¹³ and 0-3 R¹⁵, R¹³ is selectedindependently from the group consisting of —N₃, —CNO, —C(NOH)NH₂, —NHOH,—NHNHR¹⁷, —C(O)R¹⁷, —SnR¹⁷ ₃, —B(OR¹⁷)₂, and —P(O)(OR¹⁷)₂ or the groupconsisting of C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₄-C₈ alkadienyl, saidgroup being substituted with 0-2 R¹⁴, where R¹⁴ is independentlyselected from the group consisting of —NO₂, —C(O)OR¹⁷, —COR¹⁷, —CN,—OSiR¹⁷ ₃, —OR¹⁷ and —NR¹⁷ ₂; R¹⁵ is ═O, —F, —Cl, —Br, —I, —CN, —NO₂,—OR¹⁷, —NR¹⁷ ₂, —NR¹⁷—C(O)R¹⁶, —NR¹⁷—C(O)OR¹⁷, —SR¹⁷, —S(O)R ,—S(O)₂R¹⁷, —COOR¹⁷, —C(O)NR¹⁷ ₂ or —S(O)₂NR¹⁷ ₂, R¹⁶ is H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, aryl or C₁-C₆alkylene-aryl substituted with 0-3 substituents independently selectedfrom —F, —Cl, —NO₂, —R², —OR , —SiR² ₃; R¹⁷ is selected independentlyfrom the group consisting of H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl,C₁-C₆ alkylene-aryl,

G is H or C₁-C₆ alkyl and n is 1,2,3 or
 4. 3. A compound according toclaim 2 wherein, Functional entity precursor is —C(H)(R¹¹)—R¹¹′ orfunctional entity precursor is heteroaryl or aryl substituted with 0-3R¹¹, 0-3 R¹³ and 0-3 R¹⁵, wherein R¹¹ and R¹¹′0 are independently H, orselected from the group consisting of a C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₄-C₈ alkadienyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl, and heteroaryl, said group being substitutedwith 0-3 R¹², 0-3 R¹³ and 0-3 R¹⁵, or R¹¹ and R¹¹′0 are C₁-C₃alkylene-NR¹² ₂, C₁-C₃ alkylene-NR¹²C(O)R¹⁶, C₁-C₃alkylene-NR¹²C(O)OR¹⁶, C₁-C₂ alkylene-O—NR¹² ₂, C₁-C₂alkylene-O—NR¹²C(O)R¹⁶, C₁-C₂ alkylene-O—NR¹²C(O)OR¹⁶ substituted with0-3 R¹⁵, where R¹² is H or selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl, and heteroaryl, said group being substitutedwith 0-3 R¹³ and 0-3 R¹⁵, R¹³ is selected from the group consisting of—N₃, —CNO, —C(NOH)NH₂, —NHOH, —NHNHR¹⁷, —C(O)R¹⁷, —SnR¹⁷ ₃, —B(OR¹⁷)₂,and —P(O)(OR¹⁷)₂ or the group consisting of C₂-C₆ alkenyl, C₂-C₆alkynyl, and C₄-C₈ alkadienyl, said group being substituted with 0-2R¹⁴, where R¹⁴ is selected from the group consisting of —NO₂, —C(O)OR¹⁷,—COR¹⁷, —CN, —OSiR¹⁷ ₃, —OR¹⁷ and —NR¹⁷ ₂; R¹⁵ is ═O, —F, —Cl, —Br, —I,—CN, —NO₂, —OR¹⁷, —NR¹⁷ ₂, —NR¹⁷—C(O)R¹⁶, —NR¹⁷—C(O)OR¹⁶, —SR¹⁷,—S(O)R¹⁷, —S(O)₂R¹⁷, —COOR¹⁷, —C(O)NR¹⁷ ₂ or —S(O)₂NR¹⁷ ₂, R¹⁶ is H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, aryl orC₁-C₆ alkylene-aryl substituted with 0-3 substituents independentlyselected from the group consisting of —F, —Cl, —NO₂, —R², —OR², and—SiR² ₃; wherein R¹⁷ is selected independently from the group consistingof H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, and C₁-C₆ alkylene-aryl.
 4. Acompound according to claim 1 wherein, Functional entity precursor is—C(H)(R¹¹)—R¹¹′0 wherein R¹¹ and R¹¹′ are C₁-C₃ alkylene-NR¹² ₂, C₁-C₃alkylene-NR¹²C(O)R¹⁶, C₁-C₃ alkylene-NR¹²C(O)OR¹⁶, C₁-C₂ alkylene-O—NR¹²₂, C₁-C₂ alkylene-O—NR¹²C(O)R¹⁶, or C₁-C₂ alkylene-O—NR¹²C(O)OR¹⁶substituted with 0-3 R¹⁵.
 5. A compound according to claim 1 wherein,Functional entity precursor is —C(H)(R¹¹)—R¹¹′ wherein R¹¹ and R¹¹′ areindependently H, or selected from the group consisting of a C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₄-C₈ alkadienyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl, and heteroaryl, said group being substitutedwith 0-3 R¹², 0-3 R¹³ and 0-3 R¹⁵.
 6. A compound according to claim 2wherein, Functional entity precursor is —C(H)(R¹¹)—R¹¹′ wherein R¹¹ andR¹¹′ are independently H, or selected from the group consisting of aC₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, andheteroaryl, said group being substituted with 0-3 R¹² and 0-3 R¹⁵, whereR¹² is H or selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl,and heteroaryl, R¹⁵ is ═O, —F, —Cl, —Br, —I, —CN, —NO₂, —OR¹⁷, —NR¹⁷ ₂,—NR¹⁷—C(O)R¹⁶, —NR¹⁷—C(O)OR¹⁶, —SR¹⁷, —S(O)R¹⁷, —S(O)₂R¹⁷, —COOR¹⁷,—C(O)NR¹⁷ ₂ or —S(O)₂NR¹⁷ ₂, R¹⁷ is selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₁-C₆ alkylene-aryl.
 7. Acompound according to claim 1 wherein, Functional entity precursor isheteroaryl or aryl substituted with 0-3 R¹¹, 0-3 R¹³ and 0-3 R¹⁵.
 8. Acompound according to claim 2 wherein C—F-connecting group is selectedfrom the group consisting of —SO₂—O—, —O—SO₂—O—, —C(O)—O—, —S⁺(R¹¹)—,—C—U—C(V)—O—, —P⁺(W)₂—O—, and —P(W)—O— where U is —C(R²)₂—, —NR²— or—O—; V is ═O or ═NR² and W is —OR² or —N(R²)₂.
 9. A compound accordingto claim 2 wherein C—F-connecting group is —S⁺(R¹¹)—.
 10. A compoundaccording to claim 1 wherein C—F-connecting group is selected from thegroup consisting of —SO₂—O—, —O—SO₂—O—, —C(O)—O—, —S⁺(R¹⁷)—,—C—U—C(V)—O—, —P⁺(W)₂—O—, and —P(W)—O— where U is —C(R²)₂—, —NR²— or—O—; V is ═O or ═NR² and W is —OR² or —N(R²)₂, wherein R¹⁷ is H, C₁-C₆alkyl, C₃-C₇ cycloalkyl, aryl, or C₁-C₆ alkylene-aryl.
 11. A compoundaccording to wherein C—F-connecting group is chosen from the groupconsisting of —SO₂—O—, and —S⁺(R¹⁷)—; wherein R¹⁷ is H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, aryl, or C₁-C₆ alkylene-aryl.
 12. A compound accordingto claim 1 wherein, Spacer is a valence bond, C₁-C₆ alkylene-A—, C₂-C₆alkenylene-A—, C₂-C₆ alkynylene-A—, or

said spacer optionally being connected through A to a linker selectedfrom —(CH₂)_(n)—B—,

and —(CH₂)_(n)—S—S—(CH₂)_(m)—B— where A is a valence bond, —C(O)NR¹⁷—,—NR¹⁷—, —O—, —S—, or —C(O)—O—; B is a valence bond, —O—, —S—, —NR¹⁷— or—C(O)NR¹⁷— and connects to S—C-connecting group; and n and mindependently are integers ranging from 1 to 10; and R¹⁷ is H, C₁-C₆alkyl, C₃-C₇ cycloalkyl, aryl, or C₁-C₆ alkylene-aryl.
 13. A compoundaccording to claim 1 wherein, Spacer is a valence bond, C₁-C₆alkylene-A—, C₂-C₆ alkenylene-A—, C₂-C₆ alkynylene-A—, or

said spacer optionally being connected through A to a linker selectedfrom —(CH₂)_(n)—B—,

and where A is a valence bond, —C(O)NR¹⁷—, —NR¹⁷—, —S—, or —C(O)—O—; Bis —O—, —S—, —NR¹⁷—, or —C(O)NR¹⁷— and connects to S—C-connecting group;and n and m independently are integers ranging from 1 to 6; and R¹⁷ isH, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, or C₁-C₆ alkylene-aryl.
 14. Acompound according to claim 1 wherein, S—C-connecting group is a valencebond, —NH—C(═O)—,


15. A compound according to claim 2 wherein, the carrier is selectedfrom the group consisting of arylene, heteroarylene and —(CF₂)_(m)—substituted with 0-3 R¹ wherein m is an integer between 1 and 10, andC—F-connecting group is —SO₂—O—, and the functional entity precursor is—C(H)(R¹¹)—R¹¹′.
 16. A compound according to claim 1 wherein, thecarrier is —(CF₂)_(m)— wherein m is an integer between 1 and 10, theC—F-connecting group is —SO₂—O—; and the functional entity precursor isaryl or heteroaryl substituted with 0-3 R¹¹, 0-3 R¹³ and 0-3 R¹⁵.
 17. Acompound according to claim 1 wherein Complementing element is a nucleicacid.
 18. A compound according to claim 1 where Complementing element isa sequence of nucleotides selected from the group consisting of DNA,RNA, LNA PNA, and morpholino derivatives.
 19. A library of compoundsaccording to claim 1, wherein each different member of the librarycomprises a complementing element having a unique sequence ofnucleotides, which identifies the functional entity.
 20. A method fortransferring a functional entity precursor to a recipient reactivegroup, comprising the steps of providing one or more building blocksaccording to claim 1, contacting the one or more building blocks with acorresponding encoding element associated with a recipient reactivegroup under conditions which allow for a recognition between the one ormore complementing elements and the encoding elements, said contactingbeing performed prior to, simultaneously with, or subsequent to atransfer of the functional entity precursor to the recipient reactivegroup.
 21. The method according to claim 20, wherein the encodingelement comprises one or more encoding sequences comprised of 1 to 50nucleotides and the one or more complementing elements comprises asequence of nucleotides complementary to one or more of the encodingsequences.
 22. The method of claim 20, wherein the recipient reactivegroup is a nucleophilic S- or N-atom, which may be part of a chemicalscaffold, and the activating catalyst is contains palladium.